Shunji Mishiro
Department of Medical Sciences, Toshiba General Hospital,
6-3-22 Higashi Oh-i, Shinagawa-ku, Tokyo 140-8522, Japan
(Tel: 81-3-3764-8981 Fax: 81-3-3764-8992 E-mail: shunji.mishiro@po.toshiba.co.jp)
Persistent infection with hepatitis C virus (HCV) causes hepatocellular carcinoma: about 80% of hepatoma patients in Japan are HCV carriers. Hence, prevention of HCV infection as well as treatment of chronic HCV patients contribute to prevention of hepatocellular carcinoma. Interferon (IFN) has been used extensively to treat chronic hepatitis C, but its efficacy varied by viral load, viral genotypes and other factors which must include so far unknown host factors.
The IFN-inducible MXA protein is known to play an important role in the host defense against certain viruses, most of which are single-stranded RNA viruses. We aimed to see if any genetic polymorphism in the promoter region of the MXA gene is associated with the IFN-responsiveness of HCV-infected patients.
Initially we sequenced a 500-nt fragment that covers the promoter region of the MXA gene in 12 subjects, and found a single nucleotide polymorphism (SNP): G/T alleles at nt position -88. To our interest, this SNP resided within a genetic element which was highly homologous to ISRE (interferon-stimulated response element) consensus sequence, and the G-to-T change here makes this homology a little greater. When the promoter activity was compared between the G-type and T-type sequences using a luciferase reporter plasmid system, the T-type sequence exhibited much higher activity of promoting expression of the reporter gene under the presence of IFN.
In clinical settings, 63 samples from chronic hepatitis C patients who were non-responders (NR) to IFN therapy, 52 from sustained responders (SR), and 42 from healthy controls were subjected to a PCR-RFLP system which could detect this SNP (subjects were all Japanese, and unrelated). The rate of G•G homozygosity was 31% in the SR patients, significantly lower than in the NR patients (62%, P=0.0009), while that of healthy controls was an intermediate between the two groups (48%). Differences in HCV genotypes did not influence this result.
These findings suggest an scenario that the SNP of MXA promoter at nt -88 affects the level of IFN-induced expression of MXA protein, contributing to the different responsiveness of HCV patients to IFN.
Shunji Mishiro MD & PhD1973 MD University of Tokyo, Japan
1974-1975 Junior Resident, University of Tokyo Hospital, Japan
1976-1979 Research Scientist, Jichi Medical School, Japan
1980-1982 Senior Resident, University of Tokyo Hospital, Japan
1982 PhD University of Tokyo, Japan
1982-1993 Principal Research Scientist, Institute of Immunology, Japan
1994-2000 Director, Dept Medical Sciences, Toshiba General Hospital, Japan